Dor neuropática na prática clínica: ênfase nos instrumentos diagnósticos / Neuropathic pain in clinical practice: emphasis on diagnostic tools

A dor neuropática é causada por uma lesão ou doença do sistema nervoso somatossensitivo. Trata-se de uma manifestação sindrômica que envolve mecanismos inflamatórios e imunes com fisiopatologia ainda pouco esclarecida. O espectro de apresentação da dor neuropática é amplo e, assim, constitui um desafio na prática clínica. Este problema de saúde pública necessita de ampla capacidade técnica dos clínicos generalistas. Torna-se relevante identificar o potencial de cronificação do sintoma e adotar abordagens mitigantes do processo lesivo, estrutural e emocional. Nesse sentido, o diagnóstico adequado da dor neuropática é o primeiro passo na abordagem ao paciente. Diante disso, essa revisão objetiva facilitar a melhor escolha dos métodos diagnósticos no manejo clínico do paciente. Dentre estes, é possível citar a imagem por ressonância magnética funcional, eletroneuromiografia, tomografia por emissão de pósitrons, microneurografia, teste quantitativo sensorial, biópsias de pele, estudos de condução nervosa e de potencial somatossensorial evocado. A dor, por ser um processo sensorial subjetivo, apresenta amplo espectro de manifestações clínicas. Por essa razão, é possível fazer uso de técnicas como métodos de triagem e exames complementares para um diagnóstico mais específico.

Neuropathic pain is caused by an injury or illness of the somatosensory nervous system. It is a syndromic manifestation that involves inflammatory and immune mechanisms, whose pathophysiology is still poorly understood. The spectrum of presentation of neuropathic pain is wide and, therefore, it is a challenge in clinical practice. This public health problem requires the broad technical capacity of general practitioners. It is relevant to identify the potential for chronicity of the symptom and adopt mitigating approaches to the harmful, structural, and emotional process. In this sense, the proper diagnosis of neuropathic pain is the first step in approaching the patient. Therefore, this review aims to facilitate the best choice of diagnostic methods in the clinical management of the patient. Among these, functional magnetic resonance imaging, electroneuromyography, positron emission tomography, microneurography, quantitative sensory testing, skin biopsies, nerve conduction and evoked somatosensory potential studies are possible. Pain, being a subjective sensory process, has a wide spectrum of clinical manifestations. For this reason, it is possible to make use of techniques such as screening methods and complementary exams for a more specific diagnosis.

Therapeutic Effects of Resveratrol on Ischemia-Reperfusion Injury in the Nervous System.

Resveratrol is a phenol compound produced by some plants in response to pathogens, infection, or physical injury. It is well-known that resveratrol has antioxidant and protective roles in damages potentially caused by cancer or other serious disorders. Thus, it is considered as a candidate agent for the prevention and treatment of human diseases. Evidence has confirmed other bioactive impacts of resveratrol, including cardioprotective, anti-tumorigenic, anti-inflammatory, phytoestrogenic, and neuroprotective effects. Ischemia-reperfusion (IR) can result in various disorders, comprising myocardial infarction, stroke, and peripheral vascular disease, which may continue to induce debilitating conditions and even mortality. In virtue of chronic ischemia or hypoxia, cells switch to anaerobic metabolism, giving rise to some dysfunctions in mitochondria. As the result of lactate accumulation, adenosine triphosphate levels and pH decline in cells. This condition leads cells to apoptosis, necrosis, and autophagy. However, restoring oxygen level upon reperfusion after ischemia by producing reactive oxygen species is an outcome of mitochondrial dysfunction. Considering the neuroprotective effect of resveratrol and neuronal injury that comes from IR, we focused on the mechanism(s) involved in IR injury in the nervous system and also on the functions of resveratrol in the protection, inhibition, and treatment of this injury.

Nerve-associated Schwann cell precursors contribute extracutaneous melanocytes to the heart, inner ear, supraorbital locations and brain meninges.

Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.

Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause chronic and acute disease. Postacute sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys, and brain that may produce a variety of symptoms. PASC also includes a post-coronavirus disease 2019 (COVID-19) syndrome ('long COVID') with features that can follow other acute infectious diseases and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here we summarize what is known about the pathogenesis of ME/CFS and of 'acute' COVID-19, and we speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and we suggest a research agenda for both ME/CFS and post-COVID-19 syndrome.

Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system.

Ras is the most commonly mutated oncogene in humans and uses three oncogenic effectors: Raf, PI3K, and RalGEF activation of Ral. Understanding the importance of RalGEF>Ral signaling in cancer is hampered by the paucity of knowledge about their function in animal development, particularly in cell movements. We found that mutations that disrupt function of RalGEF or Ral enhance migration phenotypes of mutants for genes with established roles in cell migration. We used as a model the migration of the canal associated neurons (CANs), and validated our results in HSN cell migration, neurite guidance, and general animal locomotion. These functions of RalGEF and Ral are specific to their control of Ral signaling output rather than other published functions of these proteins. In this capacity Ral functions cell autonomously as a permissive developmental signal. In contrast, we observed Ras, the canonical activator of RalGEF>Ral signaling in cancer, to function as an instructive signal. Furthermore, we unexpectedly identified a function for the close Ras relative, Rap1, consistent with activation of RalGEF>Ral. These studies define functions of RalGEF>Ral, Rap1 and Ras signaling in morphogenetic processes that fashion the nervous system. We have also defined a model for studying how small GTPases partner with downstream effectors. Taken together, this analysis defines novel molecules and relationships in signaling networks that control cell movements during development of the nervous system.

Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses.

For thousands of years, Cannabis sativa has been utilized as a medicine and for recreational and spiritual purposes. Phytocannabinoids are a family of compounds that are found in the cannabis plant, which is known for its psychotogenic and euphoric effects; the main psychotropic constituent of cannabis is Δ9-tetrahydrocannabinol (Δ9-THC). The pharmacological effects of cannabinoids are a result of interactions between those compounds and cannabinoid receptors, CB1 and CB2, located in many parts of the human body. Cannabis is used as a therapeutic agent for treating pain and emesis. Some cannabinoids are clinically applied for treating chronic pain, particularly cancer and multiple sclerosis-associated pain, for appetite stimulation and anti-emesis in HIV/AIDS and cancer patients, and for spasticity treatment in multiple sclerosis and epilepsy patients. Medical cannabis varies from recreational cannabis in the chemical content of THC and cannabidiol (CBD), modes of administration, and safety. Despite the therapeutic effects of cannabis, exposure to high concentrations of THC, the main compound that is responsible for most of the intoxicating effects experienced by users, could lead to psychological events and adverse effects that affect almost all body systems, such as neurological (dizziness, drowsiness, seizures, coma, and others), ophthalmological (mydriasis and conjunctival hyperemia), cardiovascular (tachycardia and arterial hypertension), and gastrointestinal (nausea, vomiting, and thirst), mainly associated with recreational use. Cannabis toxicity in children is more concerning and can cause serious adverse effects such as acute neurological symptoms (stupor), lethargy, seizures, and even coma. More countries are legalizing the commercial production and sale of cannabis for medicinal use, and some for recreational use as well. Liberalization of cannabis laws has led to increased incidence of toxicity, hyperemesis syndrome, lung disease cardiovascular disease, reduced fertility, tolerance, and dependence with chronic prolonged use. This review focuses on the potential therapeutic effects of cannabis and cannabinoids, as well as the acute and chronic toxic effects of cannabis use on various body systems.

Inhibitors of angiotensin I converting enzyme potentiate fibromyalgia-like pain symptoms via kinin receptors in mice.

Fibromyalgia is a potentially disabling chronic disease, characterized by widespread pain and a range of comorbidities such as hypertension. Among the mechanisms involved in fibromyalgia-like pain symptoms are kinins and their B1 and B2 receptors. Moreover, angiotensin I converting enzyme (ACE) inhibitors, commonly used as antihypertensive drugs, can enhance pain by blocking the degradation of peptides such as substance P and bradykinin, besides enhancing kinin receptors signalling. We investigated the effect of ACE inhibitors on reserpine-induced fibromyalgia-like pain symptoms and the involvement of kinins in this effect in mice. Nociceptive parameters (mechanical and cold allodynia and overt nociception) were evaluated after ACE inhibitors administration in mice previously treated with reserpine. The role of kinin B1 and B2 receptors was investigated using pharmacological antagonism. Additionally, bradykinin levels, as well as the activity of ACE and kininase I, were measured in the sciatic nerve, spinal cord and cerebral cortex of the mice. The ACE inhibitors enalapril and captopril enhanced reserpine-induced mechanical allodynia, and this increase was prevented by kinin B1 and B2 receptor antagonists. Substance P and bradykinin caused overt nociception and increased mechanical allodynia in animals treated with reserpine. Reserpine plus ACE inhibitors increased bradykinin-related peptide levels and inhibited ACE activity in pain modulation structures. Since hypertension is a frequent comorbidity affecting fibromyalgia patients, hypertension treatment with ACE inhibitors in these patients should be reviewed once this could enhance fibromyalgia-like pain symptoms. Thus, the treatment of hypertensive patients with fibromyalgia could include other classes of antihypertensive drugs, different from ACE inhibitors.

The REACH registration process: A case study of metallic aluminium, aluminium oxide and aluminium hydroxide.

The European Union's REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.

Preoperative neurological dysfunctions: what is their meaning in patients presenting with acute type A aortic dissection?

INTRODUCTION: Type A aortic dissection (AAD) is a life-threatening disease with very high mortality. The gold standard treatment is surgical, as medical treatment has been proven to be ineffective. It is still unclear the role of preoperative neurological dysfunction in the prognosis of the patient. Therefore, the choice of performing surgery in patients with neurological symptoms is still left to the surgeon at the time of the diagnosis. The aim of this study is to make a narrative review of the current literature about the management of patients with neurological symptoms in AAD patients. EVIDENCE ACQUISITION: A bibliographical research was performed on PubMed, looking for papers containing the words: "((preoperative neurological symptoms in type a aortic dissection) OR brain injury type A aortic dissection) AND ("2010"[Date - Publication]: "3000"[Date - Publication])". A total of 35 papers were found. EVIDENCE SYNTHESIS: A total of 6 papers were chosen to be reviewed. All of them concluded that even patients with severe neurological symptoms (up to comatose state) had a good chance to recover neurological functions after surgery if treated in the first hours from the onset of symptoms. Interestingly, a hemorrhagic stroke was rarely found. CONCLUSIONS: Preoperative neurological dysfunction have been long considered a contraindication to surgery. Nevertheless, several authors show neurological and survival good results in patients with preoperative neurological dysfunction. They also stress the importance of surgical timing finding in 5 to 10 hours the surgical time limit to improve neurological dysfunction. A preoperative neurological dysfunction could be considered a strong advice towards surgical intervention. It is time to change and consider prompt surgery not only for survival but also for cerebral protection.

Clinically Actionable Strategies for Studying Neural Influences in Cancer.

Neuro-glial activation is a recently identified hallmark of growing cancers. Targeting tumor hyperinnervation in preclinical and small clinical trials has yielded promising antitumor effects, highlighting the need of systematic analysis of neural influences in cancer (NIC). Here, we outline the strategies translating these findings from bench to the clinic.

Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease.

Huwe1 is a highly conserved member of the HECT E3 ubiquitin ligase family. Here, we explore the growing importance of Huwe1 in nervous system development, function and disease. We discuss extensive progress made in deciphering how Huwe1 regulates neural progenitor proliferation and differentiation, cell migration, and axon development. We highlight recent evidence indicating that Huwe1 regulates inhibitory neurotransmission. In covering these topics, we focus on findings made using both vertebrate and invertebrate in vivo model systems. Finally, we discuss extensive human genetic studies that strongly implicate HUWE1 in intellectual disability, and heighten the importance of continuing to unravel how Huwe1 affects the nervous system.

[Effects of Enterovirus 71 on Mitochondrial Dynamics in Human Glioma U251 Cells].

OBJECTIVE: To investigate the effects of enterovirus 71 (EV71) on mitochondrial dynamics in human Glioma U251 cells. METHODS: The EV71 was replicated in Vero cells and the 50% tissue culture infective dose (TCID 50) was calculated based on the Reed-Muench formula. After the U251 cells were infected with EV71, the cellular morphology was assessed through the light microscope. The mitochondrial morphology was detected by MitoTracker Deep Red staining under laser confocal microscopy and the mitochondrial ultrastructure was visualized by transmission electron microscopy. The expressions of mitochondrial fission proteins Drp1, p-Drp1 and fusion protein Opa1 were examined by Western blot. The level of ATP was measured by a commercial ATP assay kit. The generation of mitochondrial superoxide was detected by MitoSOX staining. RESULTS: The TCID 50 of EV71 was 10 －5.4/0.1 mL. Twenty-four or 48 h after EV71 infection, the U251 cells appeared shrunken, round and dead. The laser confocal microscopy and transmission electron microscopy images showed that the EV71 infection induced mitochondrial elongation and cristae damage. Moreover, Western blot analysis demonstrated that the protein expressions of Drp1 and Opa1 were downregulated at both 24 and 48 h after EV71 infection in U251 cells, companied with a significant increase in Drp1 phosphorylation at 48 h after infection ( P<0.05). In addition, a decreased ATP level and elevated mitochondrial superoxide generation were observed in the EV71 infected group, as compared to the control group. CONCLUSION: Our study demonstrated that infection with EV71 led to changes of mitochondrial morphology and dynamics in U251 cells, which may impair mitochondrial function and contribute to nervous system dysfunction.

Riesgos prenatales, perinatales y neonatales asociados a signos neurológicos blandos / Prenatal, perinatal and neonatal risks associated with soft neurological signs

Introducción: Los signos neurológicos blandos se han asociado con dificultades motoras, alteraciones comportamentales menores e incluso como factores de vulnerabilidad para la aparición de afecciones como, esquizofrenia, trastorno de déficit de atención e hiperactividad, trastorno disocial y episodios psicóticos. Aunque la investigación sobre los signos ha venido aumentando, no se tiene claridad sobre qué puede predisponer su aparición. Objetivo: Describir la asociación entre factores de riesgo prenatales, perinatales y neonatales y la aparición de los signos neurológicos blandos en niños con estos factores riesgo y en niños sin ellos. Métodos: Estudio de tipo descriptivo comparativo, de corte transversal, con diseño no experimental. La población en estudio se conformó por 550 niños y niñas, con edades entre seis y ocho años organizados. en cuatro grupos: los que presentaban riesgos prenatales, perinatales, neonatales, y el grupo que no presentaba ningún riesgo. Las aplicaciones se llevaron a cabo durante el primer semestre de 2017. Los datos se tomaron de las historias clínicas y los. signos neurológicos blandos se evaluaron a través del apartado de la Evaluación Neuropsicológica Infantil. Resultados: La mayoría de los signos neurológicos blandos presentaron diferencias significativas y valores altos en la comparación de los rendimientos en cada uno de los grupos con riesgo. Conclusiones: la presencia de riesgos prenatales, perinatales y neonatales producen una serie de alteraciones en el desarrollo del niño que se van acumulando y pueden estar asociados con la aparición de los signos neurológicos blandos(AU)

Introduction: The soft neurological signs have been associated with motor difficulties, lower behavioural alterations and even with vulnerability factors for the appearance of conditions such as schizophrenia, attention deficit disorder and hyperactivity, disocial disorder and psychotic episodes. Although research on the signs has been increasing, it is not clear what may predispose their appearance. Objective: To describe the association between prenatal, perinatal and neonatal risk factors and the appearance of the soft neurological signs in children with these risk factors and in children without them. Methods: Descriptive, comparative, cross-sectional non-experimental design´s study. The study´s population was formed by 550 boys and girls between the ages of six and eight years organized in four groups: with prenatal risks, with perinatal risks, with neonatal risks, and the group that did not present any risks. The tests were carried out during the first semester of 2017. The data were taken from the medical records and the soft neurological signs were evaluated through the item called Neuropsychological Assessment of Children. Results: Most of the soft neurological signs showed significant differences and high values in the performance comparison in each of the groups with risks. Conclusions: The presence of prenatal, perinatal and neonatal risks produce a series of alterations in the development of the child that are accumulated and may be associated with the appearance of the soft neurological signs(AU)

Cruciate ligament healing and injury prevention in the age of regenerative medicine and technostress: homeostasis revisited.

PURPOSE: This clinical concepts paper discusses the essential elements of cruciate ligament recuperation, micro-trauma repair, and remodeling. METHODS: Cruciate ligament mechanobiology and tissue heterogeneity, anatomy and vascularity, and synovial membrane and fluid functions are discussed in relationship to deficiency-induced inflammatory responses, nervous and immune system function, recuperation, repair and remodeling, and modern threats to homeostasis. RESULTS: Cruciate ligament surgical procedures do not appreciate the vital linked functions of the central, peripheral, and autonomic nervous systems and immune system function on knee ligament injury recuperation, micro-trauma repair, and remodeling. Enhanced knowledge of these systems could provide innovative ways to decrease primary non-contact knee injury rates and improve outcomes following reconstruction or primary repair. CONCLUSIONS: Restoration of knee joint homeostasis is essential to cruciate ligament recuperation, micro-trauma repair, and remodeling. The nervous and immune systems are intricately involved in this process. Varying combinations of high-intensity training, under-recovery, technostress, and environmental pollutants (including noise) regularly expose many athletically active individuals to factors that abrogate the environment needed for cruciate ligament recuperation, micro-trauma repair, and remodeling. Current sports training practice, lifestyle psychobehaviors, and environmental factors combine to increase both primary non-contact knee injury risk and the nervous and immune system dysregulation that lead to poor sleep, increased anxiety, and poorly regulated hormone and cytokine levels. These factors may create a worst-case scenario leading to poor ligament recuperation, micro-trauma repair, and remodeling. Early recognition and modification of these factors may decrease knee ligament injury rates and improve cruciate ligament repair or reconstruction outcomes. LEVEL OF EVIDENCE: V.

Nervous system and gastric cancer.

The nervous system has been recently shown to exert impact on gastric cancer directly and indirectly. Gastric cancer cells invade nerve fibers to induce outgrowth and branching of neural cells, and nerve fibers in turn infiltrate into tumor microenvironment to promote progression of gastric cancer. Additionally, the neuro-immune interaction also plays an important role in gastric cancer development. The interplay of nerves and gastric cancer is mediated by many nervous system-associated factors, which can not only be synthesized and released by both cancer cells and nerve terminals, but also participate in regulation of many aspects of gastric cancer such as cell proliferation, angiogenesis, metastasis and recurrence. Furthermore, clinical researches indicate that some of these factors are significant diagnosis and prognosis biomarkers for gastric cancer. Herein, we reviewed recent advances and future prospects of the interaction between nervous system and gastric cancer.

Neural and endocrine mechanisms underlying stress-induced suppression of pulsatile LH secretion.

Stress is well-known to inhibit a variety of reproductive processes, including the suppression of episodic Gonadotropin releasing hormone (GnRH) secretion, typically measured via downstream luteinizing hormone (LH) secretion. Since pulsatile secretion of GnRH and LH are necessary for proper reproductive function in both males and females, and stress is common for both human and animals, understanding the fundamental mechanisms by which stress impairs LH pulses is of critical importance. Activation of the hypothalamic-pituitary-adrenal axis, and its corresponding endocrine factors, is a key feature of the stress response, so dissecting the role of stress hormones, including corticotrophin releasing hormone (CRH) and corticosterone, in the inhibition of LH secretion has been one key research focus. However, some evidence suggests that these stress hormones alone are not sufficient for the full inhibition of LH caused by stress, implicating the additional involvement of other hormonal or neural signaling pathways in this process (including inputs from the brainstem, amygdala, parabrachial nucleus, and dorsomedial nucleus). Moreover, different stress types, such as metabolic stress (hypoglycemia), immune stress, and psychosocial stress, appear to suppress LH secretion via partially unique neural and endocrine pathways. The mechanisms underlying the suppression of LH pulses in these models offer interesting comparisons and contrasts, including the specific roles of amygdaloid nuclei and CRH receptor types. This review focuses on the most recent and emerging insights into endocrine and neural mechanisms responsible for the suppression of pulsatile LH secretion in mammals, and offers insights in important gaps in knowledge.

Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study.

INTRODUCTION: Children with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children with idiopathic ASD. A complete framework is required to better understand autism in NF1, from neurobiological levels through to behavioural and functional outcomes. The primary aims of this study are to establish the frequency of ASD in children with NF1, examine the social cognitive phenotype, investigate the neuropsychological processes contributing to ASD symptoms and poor social functioning in children with NF1, and to investigate novel structural and functional neurobiological markers of ASD and social dysfunction in NF1. The secondary aim of this study is to compare the neuropsychological and neurobiological features of ASD in children with NF1 to a matched group of patients with idiopathic ASD. METHODS AND ANALYSIS: This is an international, multisite, prospective, cross-sectional cohort study of children with NF1, idiopathic ASD and typically developing (TD) controls. Participants will be 200 children with NF1 (3-15 years of age), 70 TD participants (3-15 years) and 35 children with idiopathic ASD (7-15 years). Idiopathic ASD and NF1 cases will be matched on age, sex and intelligence. All participants will complete cognitive testing and parents will rate their child's behaviour on standardised questionnaires. Neuroimaging will be completed by a subset of participants aged 7 years and older. Children with NF1 that screen at risk for ASD on the parent-rated Social Responsiveness Scale 2nd Edition will be invited back to complete the Autism Diagnostic Observation Scale 2nd Edition and Autism Diagnostic Interview-Revised to determine whether they fulfil ASD diagnostic criteria. ETHICS AND DISSEMINATION: This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.

Tumour growth activation by the central nervous system-An integrative theory of cancer.

The currently recognized mechanisms of the biology of cancer are not yet enough to explain the high incidence of the disease in industrialized countries. Survival and proliferation of cancer cells demand a well-orchestrated combination of functional capabilities, or hallmarks, which requires complex signalling networks that often exceed the tumour boundaries. Based on latest research on environmental health and aiming to provide cancer with a coherent set of organizing principles, we propose an integrative model of carcinogenesis founded on tumour growth activation by the central nervous system as an adaptive, allostatic response to both environmental and emotional challenges. In this way, chronicity of physical as well as psychological stressors may be directly involved in cancer genesis and progression, after an early inflammatory stage. The model also contemplates accidental activation of the tumour growth programme following direct DNA damage, but as a rare event that does not account for most cancers in humans. Bodily and cellular mechanisms designed to facilitate tumorigenesis may include exacerbation of the sympathetic activity, overexpression of membrane ion channels, promotion of selected mutations and methylations, degradation of the mitochondria and reprogramming of adult stem cells.

Neural activities are unfavorable for the prognosis of ovarian cancer through mRNA expression analysis.

Aim: Ovarian cancer (OC) is the leading lethal gynecological cancer in women worldwide. Understanding the molecular mechanism of OC is very important for the identification of highly sensitive biomarkers for its prognosis. Methodology: We detected prognostic-related mRNA of OC in OncoLnc database. The main features between the unfavorable and favorable prognostic OC mRNAs were analyzed and Kyoto Encyclopedia of Genes and Genomes pathway enrichment as well as correlation analysis was conducted in our study. Conclusion: Our findings suggest that neural activities can promote OC progression, indicating poor prognosis, among which axon guidance functions most significantly govern the main neural activities, followed by neurogenesis and angiogenesis. Four neural genes (NTN1, UNC5B, EFNB2 and EFNA5) could serve as promising biomarkers and therapeutic targets for precision medicine to treat OC patients.